A potential new treatment for type 2 diabetes, dapagliflozin, recently failed to gain approval from the FDA. What makes this rejection noteworthy is that the new medication works by a completely new mechanism causing the kidney to excrete sugar from the blood into the urine. Reasons for the rejection were the increased risk of bladde and breast cancer in those taking the medication, increased urine and genital infections and possible liver toxicity. That list of problems seems pretty convincing to me. This is unfortunate because the drug appears to cause weight loss and does not cause low blood sugar (hypoglycemia). However, a drug that works by “poisoning” the kidney so that it dumps sugar into the urine strikes me as a drug that is going to cause a lot of other problems.

The other established diabetes medication generating new warnings is Actos (pioglitazone). I have written a number of articles on the sister drug Avandia, defending its usefulness despite possible cardiovascular risks, but the cancer warning for Actos is a new angle on this class of drugs (thiazolidinediones). Actos has been withdrawn in France due to concerns that it may cause bladder cancer but no such action has been taken in the U.S. The FDA this month did issue a warning that individuals with bladder cancer or at risk for bladder cancer, should be advised not to use Actos. If Actos is hit hard by these actions this whole class of diabetes drugs will have been eliminated from use.
A sure sign of trouble for Actos is that a “google search” for Actos is now showing lawyer websites as the first 5 citations.

Being sick is dangerous. Treating illness also has dangers. I am concerned that our cultural zeal for uncovering scandals and for pursuing litigation will lead us to sterile treatment options and doctors who are unwilling to risk helping.

The lawsuits against Avandia are being prepared and opportunists are lining up for a payday. Unfortunately, everyone else will wind up a loser, and here’s why.

Avandia, one of only two available medicines with unique properties to treat diabetes, was approved in 1999. From the very first day Avandia was approved a heated debate arose whether Avandia or its sister drug, Actos, was the better drug for diabetes treatment. Both had similar abilities to lower blood sugar and both had the same downside of causing significant weight gain and fluid retention. Avandia showed a slightly worse effect on cholesterol profiles which convinced many diabetes specialists to choose Actos over Avandia. The choice between drugs has also been heavily influenced by cost considerations such as whether the drug was covered by the patient’s insurance carrier. I personally treated numerous patients with both drugs and found them about equal in all respects.

The lawsuits against Avandia will contend that the medication caused heart attack or stroke. The truth of this contention is very much in question, but the murkiness of the water doesn’t stop the lawyers from trying to take a bite out of the flesh of GSK (GlaxoSmithKline), the maker of Avandia.

Several years ago research studies seemed to indicate a small increased risk of heart attacks in users of Avandia. Ever since there has been a heated debate about whether this was a true risk or just the result of overly aggressive interpretation of the available data. There are two major analyzes on the subject of heart attack risk with Avandia. One, written by a doctor on the payroll of a competing drug company, looked at results from 14 thousand patients on Avandia and found a small increased risk of heart attack or stroke and the other study analyzed another 14 thousand Avandia users and found no such association. Under pressure from the public, in 2007 the FDA placed a strong warning on the label of Avandia regarding the possibility of the drug causing heart disease, but Avandia was permitted to remain on the market. The FDA warning was updated and upgraded in 2010. The publicity surrounding Avandia’s potential risks basically halted the use of the drug in the U.S.

Now enter the opportunists. Advertisements fill my email in-box from lawyers looking for customers who want to sue the drug manufacturer in class action law suits. Try goggling “Avandia side-effects” and you will find the first several pages of results are ads looking for lawsuit clients. In the last month I received two requests for patient records from these lawyers. Both patients had heart disease at the time they started the medication. One patient who recently died was over 80 years old, and the other who had significant heart disease and other diabetes complication to begin with, is still alive more than 7 years after treatment with Avandia. I wonder how much benefit these patients received from the medication which allowed them to survive as long as they did despite all the other problems they had related to their diabetes.

Why should you care about whether a small army of opportunists each get a few thousand dollars from the drug manufacturer and a few lawyers become millionaires? Because it is just this sort of legal action which is convincing drug makers to back away from developing other potential diabetes treatments. It takes a decade and a billion dollars to bring a new drug in front of the FDA. This doesn’t include the cost of developing drugs which fail to even make it to FDA review. Then the FDA approval process is tortuous and uncertain. Passing this hurdle, any new drug can come under attack (like Avandia) for “possible” side effects making the company vulnerable to devastating legal costs and bad publicity. It isn’t economically feasible to develop new diabetes drugs in the United States. As a result, new drug development is grinding to a halt. We will all suffer due to lack of innovation, not only for diabetes treatment but for treatment of many other dangerous diseases.

Diagnosing diabetes is simple. If the blood sugar is found to be elevated you are diabetic. Increasing or decreasing the cut off level between normal and diabetic will dramatically change the number of people diagnosed with diabetes. In 1997 the American Diabetes Association lowered the criterion of diabetes (type 2) to a fasting blood sugar above 126 mg/dl instead of 140 mg/dl. Suddenly 1.7 million Americans became “diabetic” under the new definition.

In the latest issue (March 24, 2011) of the New England Journal of Medicine research was published stating that Actos (pioglitazone), a popular medication used to treat type 2 diabetes, could substantially reduce the percentage of people at high risk for developing diabetes who progress to actual diabetes. 600 people with a form of pre-diabetes known as impaired fasting blood sugar (fasting blood sugar levels between 95 and 125), were divided into one group given placebo and the other group given Actos. After 2.5 years Actos reduced the incidence of developing type 2 diabetes by 72% compared to placebo. Initially, I was very impressed with these results.

Actos is the sister drug to Avandia and Rezulin. All of these drugs show similar ability to reduce blood sugar in diabetics. Rezulin and Avandia fell into disfavor due to the potential for side effects. Actos is considered safer.

It seems almost a little too obvious that if diabetes is defined as elevated blood sugar that if the test medication reduces blood sugar, diabetes can be “prevented”. Since Actos lowers blood sugar, the conclusion that Actos reduces the progression of pre-diabetes to actual diabetes seems inevitable. A substance that does not already lower blood sugar which prevented elevated blood sugar from developing would be far more impressive.

Side-effects of taking Actos need to be considered, as well. In this research study (New England J of Medicine 364; 12, 2011) the group taking Actos gained an average of about 9 pounds. That doesn’t include the 3% of test subjects who dropped out of the study because they gained too much weight. Edema (puffy ankles) was also more common in those taking Actos. We know that weight gain, particularly in pre-diabetics, is not a good thing. What are we hoping to accomplish by using Actos to prevent diabetes when at the same time, we make people chunkier and puffier?

To be fair, the family of medications known as “glitazones” which contain Actos, Avandia and Rezulin, have some intriguing properties. Years ago, the Triad Study, showed that women with gestational diabetes who received Rezulin, did not go on to develop type 2 diabetes nearly as often, even years after stopping this medication. This does seem like a true preventive benefit.

I am dubious about using Actos to prevent diabetes at this time. My patients, I suspect, will agree with that decision. I don’t think I would survive very long in practice, if my patients gain 10 or more pounds as I try to “prevent” their progression to diabetes.

This information is for educational purposes only and is not intended as medical advise or treatment. Always consult with your physician when deciding whether to use a prescription drug.

Over the years the medicinal qualities of vitamin E have been both praised and criticized. For decades there has been a debate whether this vitamin could prevent cancer or heart disease. Large studies have pretty much determined that cancer and heart disease don’t respond to vitamin E supplementation. For that reason many physicians believe that vitamin E treatment is worthless for any purpose. This assumption is incorrect. For example, a recent study in the New England of Medicine has shown vitamin E to be of great use in the treatment of a common liver disease resulting from fat accumulation in the liver (steatosis).

The liver normally store some fat but in excess it can lead to inflammation of the liver, a condition called steatohepatitis. In up to 15% of those with steatohepatitis, cirrhosis and liver failure can result. Steatohepatitis itself is relatively common. In my endocrinology practice several patients per day show evidence of this liver disease, manifested as abnormalities on routine liver blood tests. Patients most likely to show characteristic abnormalities on liver blood tests are those with high cholesterol (particularly if taking the cholesterol lowering medications known as statins), diabetes, and obesity. If the blood tests are particularly abnormal an ultrasound of the liver is usually obtained to be sure nothing else is occurring, such as liver cancer or cirrhosis. Simple steatosis itself is generally easy to diagnose on the ultrasound.

A recent study in the New England Journal of Medicine (Volume 362, No. 18) demonstrates that vitamin E is beneficial for treating steatohepatitis. 247 subjects with evidence of steatohepatitis not due to alcohol use or diabetes were given various treatments. The group getting 800 IU vitamin E per day showed a 43% improvement in measures of steatohepatitis. Also examined as a possible treatment for steatohepatitis was Actos (pioglitazone), a popular diabetes drug. Although the results with Actos were promising they weren’t as good as the results with Vitamin E.

As always, the researchers conclude that further studies will be needed to confirm this benefit. Before using vitamin E in your own program be sure to check with your physician first. Vitamin E can act like a blood thinner, so its use in people who have bleeding abnormalities or on drugs that influence blood clotting, is of particular concern.

This article is for educational purposes only and is not intended as medical advice. The disclaimer for metabolism.com applies to this and all my posts.

In 2007 I published an article entitled, “Old News About Avandia and Actos Makes Front Page New York Times”. This article criticized the media for publishing an old story about the potential danger of Avandia, then a popular diabetes medication. Even in 2007 the potential hazard of Avandia was a story which had been beaten to death by experts with the conclusion that the hazard of using this drug was probably exaggerated by a few vocal critics. Since then much more information has come to light supportive of the safety of using Avandia. Just a week ago the whole issue again made front page news, making it seem as if something new had come to light on the safety issue. Close inspection of the reports show this to be virtually the same information that existed in 2007 without the benefit of more recent information, but now rehashed by a congressional committee. So here we have it…old, old news making headlines again but unenlightened by the passage of another 3 years.

Here is the original story about “old news” which I published at metabolism.com in 2007

Old News About Avandia and Actos Makes the Front Page NY Times

Today’s NY Times carries a front page article about the dangers of Actos and Avandia, two popular diabetes medications. The reason behind the news story is that the FDA has finally required the two companies that make these diabetes drugs to carry a “black box” warning (the strongest labeling warning that can be applied) about the potential for congestive heart failure (overload of fluid in the heart and lungs) in diabetics using these drugs. Is this warning really news? Not to doctors.

I have been to numerous seminars on the use of these two diabetes drugs and have been paid by the companies that manufacture these drugs to educate other health care professionals about the use and hazards of these drugs. Both companies gave all representatives and speakers the strictest instructions regarding their obligation to carefully mention the potential for fluid overload and congestive heart failure associated with the use of these drugs. I know that my colleagues, particularly the cardiologists (heart doctors) and endocrinologists (diabetes doctors), have been acutely aware of this information for years.

Did you know that the type of drugs known as sulfonylureas that have been used to treat diabetes since the 1960’s and remain popular today carry a “black box” warning since the 1970’s about the potential for causing heart disease? This class of drug include Diabinese, Orinase, DiaBeta, Micronase, glyburide, and glipizide. Why are these drugs still in widespread use, and where are the stories notifying the public about this? What’s the big deal about the black box warning on Actos and Avandia?

I think I smell some politics going on. The Commissioner of the FDA, Dr. von Eschenback, was appointed by President Bush in 2005. The harshest critics of the FDA on this issue are the Democrats on the House Panel. Coming out of the woodwork are various “injured” parties who were criticised by company representatives for speaking out against these drugs in 1999. These stories warrant a separate column in The Times today.

Are there real risks to taking Actos and Avandia in the treatment of diabetes. Of course there are, just as there is a real risk of treating diabetes with just about any drug. It is up to the medical profession to remain vigilant and educated about these risks and to balance them with the benefits. Inflammatory front page news stories which create an atmosphere of mistrust and hysteria may serve only narrow political purposes.

This blogged comment at metabolism.com is not intended to convey medical advice. Diabetics are encouraged to contact their own healthcare professional about advice about what to do at this time. Most authorities encourage the public not to panic and to wait instructions from their physician before altering their medical treatment.

Recently the American Academy of Clinical Endocrinologists issued new treatment guidelines for treating Type 2 Diabetes. Complex medical guidelines are often referred to as a treatment algorithm. One of the stated goals of the AACE algorithm is to focus primarily on the theoretical ability of the diabetic medications to control blood sugar while ignoring the cost of the medication. The rationale to this approach is that controlling blood sugar with more expensive drugs will cost less in the long run since patients will be healthier and have less complications due better control of the blood sugar. On the surface this philosophy seems sound but digging beneath the surface reveals dangerous flaws in this thinking.

1. The first assumption, that newer medications for diabetes are better than older drugs is unsubstantiated. In fact there is ample evidence that newer diabetic drugs are no better than the older drugs for controlling blood sugar. The latest study finding no benefit of the newer diabetes medications is the FIELD study conducted outside of the U.S. This study showed that 5 years of treatment with the older diabetic drugs (sulfonylureas, metformin and insulin) resulted in adequate and prolonged control of blood sugar. In 2007 researchers from Johns Hopkins Bloomberg School of Public Health summarized the results of major studies using older and newer anti-diabetic medications and found no significant benefit of the newer medications.

2. The next assumption, that cost is not a key factor in treatment success contradicts most clinicians’ experience in diabetes care. It is clear to me, that patients are far less likely to comply with using expensive drugs than medications they can more easily afford. Looking at the numbers reveals the vast cost differences between the older (generic) versus the newer (brand) medications. Using figures provided by a local pharmacy I found that the retail cost of a typical two drug therapy for diabetes using older drugs is $59 per month. The retail cost of using two of the new drugs for a month ranges from $481 to $570. In more severe diabetes three drugs per day may be needed. The low cost alternative amounts to $185 per month while the high end alternative with new drugs is $610 per month. Looking at the cost of using insulin shows a similar vast cost difference between the older and newer drugs. Older forms of insulin may cost $100 for a month’s supply while a similar course of therapy with the newer insulin preparations will cost almost $250 per month. How many people will be willing and able to afford the new versus the old drugs, particularly knowing that there may be no health benefit to the more expensive drug combination?

The end result of not being able to afford these prices is non-compliance with medications and the result of non-compliance is higher costs passed on to the medical system. The Medco study from 2005 showed that the least compliant patients were more than twice as likely to be hospitalized compared to the most compliant, and that the yearly cost of caring for non-compliant patients is double that of compliant patients.

3. My next point is possibly the most contentious. The AACE guidelines were produced by a committee of physicians chaired by two distinguished endocrinologists, Dr. Paul Jellinger and Dr. Helena Rodbard. Both doctors are highly respected and accomplished. They are also both highly compensated consultants to the pharmaceutical companies which market the newest generation of diabetes medications. In the disclaimer attached to the committee’s recommendations, both Dr. Jellinger and Dr. Rodbard admit to consulting arrangements with virtually every one of the pharmaceutical companies whose interests are effected by their committee’s findings. I too am a consultant to many of these same companies (at least, until now), but I am not responsible for developing national guidelines for diabetes care. In my opinion the close association of both committee chairmen to the pharmaceutical companies detracts heavily from the credibility of their recommendations. The need for credibility is even more important when the AACE committee advises physicians to avoid using sulfonylureas, the only class of drugs not marketed by any of the big pharma companies. and which also happens to be the cheapest drug class, the drugs with the longest history of use, and the class of drugs many regard as the most effective at lowering blood sugar levels. The sulfonylurea class of drugs is so effective at lowering blood sugar, in fact, they are used as the gold standard by which the effectiveness of all new diabetic medications are compared.

4. In contrast with the AACE, the American Diabetes Association (ADA) has issued more conservative guidelines for diabetic therapy, preserving the role of the older generic drugs. My recommendation is that AACE go back to their committee and reconsider the way they have produced their algorithm. Appointing new leadership whose credentials do not lend themselves so readily to skepticism, would be an important first step in that process.

Gary Pepper, M.D.
Editor-in-Chief, Metabolism.com

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Actos, released this summer by Lilly and Co. in collaboration with Takeada Pharmaceuticals, is the latest of the oral agents for treatment of diabetes. Actos whose chemical name is pioglitazone, is part of the new class of diabetes fighting drugs called “glitazones”. Other drugs in this class are Rezulin(Parke Davis/Sankyo) and Avandia (Bristol Myers Squibb). Glitazones work by making the body more sensitive to insulin. This is important because diabetes develops in up to 92% of Type 2 Diabetics (adult onset variety) due to an impairment of the body’s ability to utilize the insulin already in the blood. This defect is called insulin resistance and is a genetically determined (inherited) characteristic. Certain drugs such as steroids (Prednisone, cortisone) can make insulin resistance worse as can obesity.

Use alone or in combination

Actos can be used alone or in combination with a variety of other diabetes treatments. Many diabetics are already taking pills of a type known as sulfonylureas, including Glucotrol, Amaryl, Prandin, Micronase and Diabeta. Glitazones such as Actos can be combined with these to create an enhancement of the blood sugar lowering effect. What’s more Actos can be combined with the other classes of anti-diabetes drugs including Glucophage (metformin) and even insulin itself. Some Type 2 diabetics who are taking insulin can have their insulin doses reduced or even eliminated after starting Actos.

Generally safe to use

The first glitazone released over 2 years ago, Rezulin, received a lot of negative attention due to its association with a rare but potentially lethal side effect of liver failure. Fortunately there is no indication so far that the two newest glitazones, Actos and Avandia, produce this complication. Both new glitazones can cause fluid retention and should be used with great caution in individuals with heart failure.

Can improve cholesterol levels

An additional benefit to Actos is its ability to improve the abnormal cholesterol (lipid) profile usually seen with Type 2 diabetes. High triglyceride levels with low HDL (good cholesterol) and high LDL (bad cholesterol) is a common combination of lipid abnormalities in diabetics. Actos has been shown to lower triglyceride levels by about 10%, raise HDL by about 20% and have a neutral effect on LDL. Only Rezulin has shown similar beneficial effects among the glitazones.

Actos is a great addition to the available drugs for treatment of diabetes. As always, consult with your health care provider before embarking on any changes in your treatment regime.

We gratefully acknowledge that this page is supported in part by a grant from the Eli Lilly company

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Today’s NY Times carries a front page article about the dangers of Actos and Avandia, two popular diabetes medications. The reason behind the news story is that the FDA has finally required the two companies that make these diabetes drugs to carry a “black box” warning (the strongest labeling warning that can be applied) about the potential for congestive heart failure (overload of fluid in the heart and lungs) in diabetics using these drugs. Is this warning really news? Not to doctors.

I have been to numerous seminars on the use of these two diabetes drugs and have been paid by the companies that manufacture these drugs to educate other health care professionals about the use and hazards of these drugs. Both companies gave all representatives and speakers the strictest instructions regarding their obligation to carefully mention the potential for fluid overload and congestive heart failure associated with the use of these drugs. I know that my colleagues, particularly the cardiologists (heart doctors) and endocrinologists (diabetes doctors), have been acutely aware of this information for years.

Did you know that the type of drugs known as sulfonylureas that have been used to treat diabetes since the 1960’s and remain popular today carry a “black box” warning since the 1970’s about the potential for causing heart disease? This class of drug include Diabinese, Orinase, DiaBeta, Micronase, glyburide, and glipizide. Why are these drugs still in widespread use, and where are the stories notifying the public about this? What’s the big deal about the black box warning on Actos and Avandia?

I think I smell some politics going on. The Commissioner of the FDA, Dr. von Eschenback, was appointed by President Bush in 2005. The harshest critics of the FDA on this issue are the Democrats on the House Panel. Coming out of the woodwork are various “injured” parties who were criticised by company representatives for speaking out against these drugs in 1999. These stories warrant a separate column in The Times today.

Are there real risks to taking Actos and Avandia in the treatment of diabetes. Of course there are, just as there is a real risk of treating diabetes with just about any drug. It is up to the medical profession to remain vigilant and educated about these risks and to balance them with the benefits. Inflammatory front page news stories which create an atmosphere of mistrust and hysteria may serve only narrow political purposes.

This blogged comment at metabolism.com is not intended to convey medical advice. Diabetics are encouraged to contact their own healthcare professional about advice about what to do at this time. Most authorities encourage the public not to panic and to wait instructions from their physician before altering their medical treatment.